Submissions for variant NM_000388.4(CASR):c.101T>C (p.Leu34Pro)

dbSNP: rs1559955362

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000711027	SCV000841346	uncertain significance	not provided	2018-02-06	criteria provided, single submitter	clinical testing
Invitae	RCV001231195	SCV001403706	uncertain significance	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-06-05	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 585617). This variant has not been reported in the literature in individuals affected with CASR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 34 of the CASR protein (p.Leu34Pro).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003225115	SCV003921996	likely pathogenic	Neonatal severe primary hyperparathyroidism	2021-05-07	criteria provided, single submitter	clinical testing	0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene and are associated with CASR-related disease (OMIM). Truncating variants predicted to undergo nonsense-mediated decay, and missense variants with either a dominant negative or loss of function effect on protein function, have been reported to cause hypocalciuric hypercalcemia, type I (MIM#145980), and neonatal hyperparathyroidism (MIM#239200). Missense variants that have a gain of function effect on protein activity, have been reported to cause hypocalcemia, with or without Barrter syndrome (MIM#601198) (OMIM, PMID: 22422767, PMID: 26646938, PMID: 16649980). (I) 0108 - This gene is associated with both recessive and dominant disease. Recessive disease is caused by biallelic loss of function variants, and results in neonatal hyperparathyroidism (MIM#239200) (OMIM, PMID: 22422767, PMID: 26646938). (I) 0115 - Variants in this gene are known to have variable expressivity. Members of the same family have been reported to exhibit either hypercalcemia, hypocalciuric or hypercalciuric (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ligand binding domain (NCBI, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported twice as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (p.(Asn64Asp)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV000711027	SCV004155402	likely pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	CASR: PM1, PM2, PP3, PP4